Composition and kit comprising piperazine derivatives and metformin, and use thereof in the treatment of diabetes

ABSTRACT

The present invention relates to a composition comprising, in combination, metformin or a salt thereof, a pharmaceutically acceptable carrier or excipient and at least one compound of formula (I), the enantiomers, diastereoisomers or pharmaceutically acceptable salts thereof. Formula (I). The present invention also relates to the use of said composition for the treatment of diseases associated with insulin resistance syndrome.

The present invention pertains to compositions and a kit comprising inassociation at least one derivative of piperazine or thepharmaceutically salts thereof and metformin or the pharmaceuticallyacceptable salts thereof, and to their uses in particular in thetreatment of pathologies associated with insulin-resistance syndrome (orsyndrome X) particularly in the treatment of Type 2 diabetes.

In recent years a major increase has been observed in the number ofcases of diabetes across the world. In 2011, there were around 366million diabetics in the world and the prediction for 2030 is in theorder of over 550 million diabetics. Type 2 diabetes (destruction ofinsulin-producing cells) is chiefly treated with injection of insulin.Type 2 diabetes which is the most widespread (90% of diabetes cases) ischaracterized by tissue resistance to insulin and requires specialtreatment.

Numerous compounds have been proposed for the treatment of diabetes, andin particular of Type 2 diabetes. In particular, from documentderivatives of piperazine are known. Also phenyl derivatives are knownfrom WO02/100341.

At the current time, in about 40% of cases, treatment is not effectiveand the desired fasting glycaemia threshold of 1.26 g/litre of blood isnot reached.

In addition, more than 40% of treated patients have a glycosylatedhaemoglobin level (HbA1c) higher than 7%, in particular after atreatment time of several years.

There is therefore a need for novel associations allowing more efficienttreatment of pathologies associated with insulin-resistance syndrome andwhich limits phenomena of resistance to active ingredients.

It is therefore one objective of the invention to provide efficientcompositions and associations for the treatment of pathologiesassociated with insulin-resistance syndrome. Another objective of thepresent invention is to propose compositions and associations allowingthe inhibition of neoglucogenesis in particular.

A further objective of the present invention is to provide means fortreating pathologies associated with insulin-resistance syndrome, and inparticular Type 2 diabetes.

Other objectives will become apparent on reading the followingdescription of the invention.

These objectives are met with the present invention which proposes acomposition comprising in association metformin or a metformin salt andat least one compound of formula (I) and the enantiomers,diastereoisomers and pharmaceutically acceptable salts thereof:

where:

R¹ is a group from among:

-   -   —C(O)CR³R⁴CR⁵R⁶C(O)OH;    -   —C(OH)(H)CR³R⁴CR⁵R⁶C(O)OH;    -   —(CH₂)₄C(O)OH; or

m is an integer ranging from 0 to 8;

n is 0 or 1;

L¹ is a group from among —C(O)—, —C(O)O— or —S(O)₂—;

R² is:

-   -   5-, 6- or 7-membered carbocycle group, saturated, partly        unsaturated or aromatic, substituted or unsubstituted;    -   8- to 14-membered polycarbocycle group, preferably 9 or        10-membered, saturated, partly unsaturated or aromatic,        substituted or unsubstituted;    -   5-, 6- or 7-membered heterocycle group, substituted or        unsubstituted, saturated, partly unsaturated or aromatic        possibly having 1, 2 or 3 heteroatoms, the same or different        selected in particular from among nitrogen, oxygen or sulfur;    -   8- to 14-membered polyheterocycle group, preferably 9- or        10-membered, substituted or unsubstituted, saturated, partly        unsaturated or aromatic possibly having 1, 2 or 3 heteroatoms,        the same or different, selected in particular from among        nitrogen, oxygen or sulfur;    -   -L²-carbocycle group, the carbocycle being 5-, 6- or 7-membered,        saturated, partly unsaturated or aromatic, substituted or        unsubstituted;    -   -L²-polycarbocycle group, the polycarbocycle being 8- to        14-membered, preferably 9- or 10-membered, saturated, partly        unsaturated or aromatic, substituted or unsubstituted;    -   -L²-heterocycle group, the heterocycle being 5-, 6- or        7-membered, substituted or unsubstituted, saturated, partly        unsaturated or aromatic and possibly having 1, 2 or 3        heteroatoms, the same or different, selected in particular from        among nitrogen, oxygen or sulfur;    -   -L²-polyheterocycle group, the polyheterocycle being 8- to        14-membered, preferably 9- or 10-membered, substituted or        unsubstituted, saturated partly unsaturated or aromatic possibly        having 1, 2 or 3 heteroatoms, the same or different, selected in        particular from among nitrogen, oxygen or sulfur; or    -   hydrocarbon group, straight-chain or branched, C₁ to C₅,        preferably C₁ to C₄, preferably alkyl, straight-chain or        branched, C₁ to C₅, preferably C₁ to C₄;

L² representing an alkyl, straight-chain or branched, C₁ to C₅,preferably C₁ to C₄;

R³, R⁴, R⁵ and R⁶, the same or different, are:

-   -   a hydrogen atom;    -   an alkyl group, straight-chain or branched, C₁ to C₅, preferably        C₁ to C₄;    -   5-, 6- or 7-membered carbocycle group, saturated, partly        unsaturated or aromatic, substituted or unsubstituted; or

R₃ and R₄, together with the carbon atom to which they are attached,form a 5-, 6- or 7-membered carbocycle, substituted or unsubstituted,preferably saturated; e.g. cyclopentyl, cyclohexyl; or

R₅ and R₆, together with the carbon atom to which they are attached,form a 5-, 6- or 7-membered carbocycle, substituted or unsubstituted,preferably saturated; e.g. cyclopentyl, cyclohexyl;

R⁷, the same or different, are:

-   -   an alkyl, straight-chain or branched, C₁ to C₅, preferably C₁ to        C₄; e.g. methyl, ethyl, propyl, iso-propyl, butyl, ter-butyl;    -   -L²-carbocycle group, the carbocycle being 5-, 6- or 7-membered,        saturated, partly unsaturated or aromatic, substituted or        unsubstituted;    -   -L²-polycarbocycle group, the polycarbocycle being 8- to        14-membered, preferably 9- or 10-membered, saturated partly        unsaturated or aromatic substituted or unsubstituted;    -   -L²-heterocycle group, the heterocycle being 5-, 6- or        7-membered, substituted or unsubstituted, saturated, partly        unsaturated or aromatic, and possibly having 1, 2 or 3        heteroatoms, the same or different, selected in particular from        among nitrogen, oxygen or sulfur; or    -   -L²-polyheterocycle group, the polyheterocycle being 8- to        14-membered, preferably 9- or 10-membered, substituted or        unsubstituted, saturated, partly unsaturated or aromatic and        possibly having 1, 2 or 3 heteroatoms, the same or different,        selected in particular from among nitrogen, oxygen or sulfur.

The carbocycles, polycarbocycles, heterocycles and polyheterocycles areunsubstituted or substituted by one or more substituents, the same ordifferent, selected in particular from among:

-   -   C₁ to C₆ alkoxy group, straight-chain or branched, e.g. methoxy,        ethoxy, propoxy, iso-propoxy, butoxy, ter-butoxy;    -   a halogen atom;    -   a hydrocarbon group, straight-chain or branched, preferably        alkyl, C₁ to C₅, preferably C₁ to C₄, e.g. methyl, ethyl,        propyl, butyl, iso-propyl, ter-butyl;    -   a hydrocarbon group, straight-chain or branched, preferably        alkyl, C₁ to C₅, preferably C₁ to C₄, substituted in particular        by one more halogen atoms;    -   a cyano group (—CN);    -   an alkyl sulfonyl group (—S(O)₂-alkyl) wherein the alkyl is        straight-chain or branched, C₁ to C₅, preferably C₁ to C₄, e.g.        methyl, ethyl, propyl, butyl, iso-propyl, ter-butyl; or    -   5, 6 or 7-membered carbocycle group, saturated, partly        unsaturated or aromatic, preferably phenyl, unsubstituted or        substituted in particular by one or more substituents, the same        or different, selected in particular from among a halogen atom,        C₁ to C₆ alkoxy group, straight-chain or branched e.g. methoxy,        ethoxy, propoxy, iso-propoxy, butoxy, ter-butoxy; C₁ to C₅ alkyl        group preferably C₁ to C₄, e.g. methyl, ethyl, propyl, butyl,        iso-propyl, ter-butyl.

Preferably, in the formula (I) compound, R⁷, the same or different, are:

-   -   C₁ to C₃ alkyl, straight-chain or branched, or    -   -L²-carbocycle group, L² being an alkyl, straight-chain or        branched, C₁ to C₅, preferably C₁ to C₄; and the carbocycle        being aromatic with 5 or 6 members, e.g. phenyl, optionally        substituted.

Preferably in the formula (I) compound, m is 0 or 1, preferably 0.

Preferably, in the formula (I) compound, R² is:

-   -   a 6-membered aromatic carbocyle group, unsubstituted or        substituted by one or more substituents, the same or different,        selected in particular from among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched, e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom, e.g. fluorine, chlorine, bromine;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched e.g. methyl, ethyl, propyl, butyl, iso-propyl,            ter-butyl;        -   C₁ {dot over (a)} C₅ alkyl group, preferably C₁ to C₄,            straight-chain or branched, substituted in particular by one            or more halogen atoms e.g. trifluoromethyl;        -   cyano group (—CN);        -   alkylsulfonyl group (—S(O)₂-alkyl) wherein the alkyl is            straight-chain or branched, C₁ to C₅, preferably C₁ to C₄,            e.g. methyl, ethyl, propyl, butyl, iso-propyl, ter-butyl            e.g. methane sulfonyl (—S(O)₂CH₃); or        -   aryl group, preferably phenyl, unsubstituted or substituted            in particular by one or more substituents, the same or            different, selected in particular from among a halogen atom,            C₁ to C₆ alkoxy group, straight-chain or branched e.g.            methoxy, ethoxy, propoxy, iso-propoxy, butoxy, ter-butoxy; a            C₁ to C₅ alkyl group, preferably C₁ to C₄, e.g. methyl,            ethyl, propyl, butyl, iso-propyl, ter-butyl;    -   an aromatic heterocycle group with 5 or 6 members, having 1, 2        or 3 heteroatoms, the same or different, selected in particular        from among nitrogen, sulfur and oxygen, unsubstituted or        substituted by one or more substituents, the same or different        selected in particular from among:    -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain or        branched e.g. methoxy, ethoxy, propoxy, iso-propoxy, butoxy,        ter-butoxy;    -   a halogen atom e.g. fluorine, chlorine, bromine;    -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or        branched e.g. methyl, ethyl, propyl, butyl, iso-propyl,        ter-butyl;    -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or        branched, substituted in particular by one or more halogen atoms        e.g. trifluoromethyl;    -   cyano group (—CN);    -   an alkylsulfonyl group (—S(O)₂-alkyl) wherein the alkyl is        straight-chain or branched,

C₁ to C₅, preferably C₁ to C₄ e.g. methyl, ethyl, propyl, butyl,iso-propyl, ter-butyl e.g. methane sulfonyl (—S(O)₂CH₃); or

-   -   an aryl group, preferably phenyl, unsubstituted or substituted        in particular by one or more substituents, the same or        different, selected in particular from among a halogen atom, C₁        to C₆ alkoxy group, straight-chain or branched e.g. methoxy,        ethoxy, propoxy, iso-propoxy, butoxy, ter-butoxy; C₁ to C₅ alkyl        group preferably C₁ to C₄ e.g. methyl, ethyl, propyl, butyl,        iso-propyl, ter-butyl;

preferably the heterocycle is unsubstituted or substituted by a phenylgroup unsubstituted or substituted in particular by one or moresubstituents, the same or different, selected in particular from among ahalogen atom, C₁ to C₆ alkoxy group, straight-chain or branched e.g.methoxy, ethoxy, propoxy, iso-propoxy, butoxy, ter-butoxy; C₁ to C₅alkyl group, preferably C₁ to C₄, e.g. methyl, ethyl, propyl, butyl,iso-propyl, ter-butyl;

-   -   8- to 14-membered aromatic polyheterocycle, preferably 9- or        10-membered, having 1, 2 or 3 heteroatoms, the same or        different, selected from among nitrogen, sulfur and oxygen,        unsubstituted or substituted by one or more substituents, the        same or different, selected in particular from among:    -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain or        branched e.g. methoxy, ethoxy, propoxy, iso-propoxy, butoxy,        ter-butoxy;    -   a halogen atom e.g. fluorine, chlorine, bromine;    -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or        branched e.g. methyl, ethyl, propyl, butyl, iso-propyl,        ter-butyl;    -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or        branched, substituted in particular by one or more halogen atoms        e.g. trifluoromethyl;    -   a cyano group (—CN);    -   an alkylsulfonyl group (—S(O)₂-alkyl) wherein the alkyl is        straight-chain or branched, C₁ to C₅, preferably C₁ to C₄, e.g.        methyl, ethyl, propyl, butyl, iso-propyl, ter-butyl, e.g.        methane sulfonyl (—S(O)₂CH₃); or    -   an aryl group, preferably phenyl, unsubstituted or substituted        in particular by one or more substituents, the same or        different, selected in particular from among a halogen atom, C₁        to C₆ alkoxy group, straight-chain or branched e.g. methoxy,        ethoxy, propoxy, iso-propoxy, butoxy, ter-butoxy; C₁ to C₅ alkyl        group, preferably C₁ to C₄, e.g. methyl, ethyl, propyl, butyl,        iso-propyl, ter-butyl;    -   an alkyl group, straight-chain or branched, C₁ to C₅, preferably        C₁ to C₄, e.g. methyl, ethyl, propyl, butyl, iso-propyl,        ter-butyl; or    -   -L²-carbocycle group, the carbocycle being aromatic with 5 or 6        members, e.g. phenyl, unsubstituted or substituted by one or        more substituents, the same or different, selected in particular        from among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom e.g. fluorine, chlorine, bromine;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched e.g. methyl, ethyl, propyl, butyl, iso-propyl,            ter-butyl;        -   C₁ to C₅, alkyl group, preferably C₁ to C₄, straight-chain            or branched, substituted in particular by one or more            halogen atoms e.g. trifluoromethyl;        -   a cyano group (—CN);        -   an alkylsulfonyl group (—S(O)₂-alkyl) wherein the alkyl is            straight-chain or branched, C₁ to C₅, preferably C₁ to C₄,            e.g. methyl, ethyl, propyl, butyl, iso-propyl, ter-butyl,            e.g. methane sulfonyl (—S(O)₂CH₃); or        -   an aryl group, preferably phenyl, unsubstituted or            substituted in particular by one or more substituents, the            same or different, selected in particular from among a            halogen atom, C₁ to C₆ alkoxy group, straight-chain or            branched e.g. methoxy, ethoxy, propoxy, iso-propoxy, butoxy,            ter-butoxy; C₁ to C₅ alkyl group, preferably C₁ to C₄, e.g.            methyl, ethyl, propyl, butyl, iso-propyl, ter-butyl;

L² being an alkyl group, straight-chain or branched, C₁ to C₅,preferably C₁ to C₄, e.g. methyl, ethyl, propyl, butyl, iso-propyl,ter-butyl.

Preferably, in the formula (I) compound, R² is:

-   -   a phenyl, unsubstituted or substituted by one or more        substituents, the same or different, selected in particular from        among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom e.g. fluorine, chlorine, bromine;        -   C₁ {dot over (a)} C₅ alkyl group, preferably C₁ to C₄,            straight-chain or branched e.g. methyl, ethyl, propyl,            butyl, iso-propyl, ter-butyl;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched, substituted in particular by one or more halogen            atoms e.g. trifluoromethyl;        -   a cyano group (—CN);        -   an alkylsulfonyl group (—S(O)₂-alkyl) wherein the alkyl is            straight-chain or branched, C₁ to C₅, preferably C₁ to C₄,            e.g. methyl, ethyl, propyl, butyl, iso-propyl, ter-butyl,            e.g. methane sulfonyl (—S(O)₂CH₃); or        -   a phenyl group, unsubstituted or substituted in particular            by one or more substituents, the same or different, selected            in particular from among a halogen atom, C₁ to C₆ alkoxy            group, straight-chain or branched, e.g. methoxy, ethoxy,            propoxy, iso-propoxy, butoxy, ter-butoxy; C₁ to C₅ alkyl            group, preferably C₁ to C₄, e.g. methyl, ethyl, propyl,            butyl, iso-propyl, ter-butyl;

preferably the substituent(s) are at ortho or para position on thephenyl;

-   -   a monocyclic or polycyclic heteroaryl selected from among

-   -   unsubstituted or substituted by one or more substituents, the        same or different, selected in particular from among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched, e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom e.g. fluorine, chlorine, bromine;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched e.g. methyl, ethyl, propyl, butyl, iso-propyl,            ter-butyl;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched, substituted in particular by one or more halogen            atoms e.g. trifluoromethyl;        -   a cyano group (—CN);        -   an alkylsulfonyl group (—S(O)₂-alkyl) wherein the alkyl is            straight-chain or branched, C₁ to C₅, preferably C₁ to C₄,            e.g. methyl, ethyl, propyl, butyl, iso-propyl, ter-butyl            e.g. methane sulfonyl (—S(O)₂CH₃); or        -   a pheny group, unsubstituted or substituted in particular by            one or more substituents, the same or different, selected in            particular from among a halogen atom, C₁ to C₆ alkoxy group,            straight-chain or branched e.g. methoxy, ethoxy, propoxy,            iso-propoxy, butoxy, ter-butoxy; C₁ to C₅ alkyl group,            preferably C₁ to C₄, e.g. methyl, ethyl, propyl, butyl,            iso-propyl, ter-butyl;

preferably the mono or polycyclic heteroaryl is selected from among:

-   -   -L²-carbocycle group, the carbocycle being a phenyl        unsubstituted or substituted by one or more substituents, the        same or different, selected in particular from among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom e.g. fluorine, chlorine, bromine;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched e.g. methyl, ethyl, propyl, butyl, iso-propyl,            ter-butyl;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched, substituted in particular by one or more halogen            atoms e.g. trifluoromethyl;        -   a cyano group (—CN);        -   an alkylsulfonyl group (—S(O)₂-alkyl) wherein the alkyl is            straight-chain or branched, C₁ to C₅, de preferably C₁ to C₄            e.g. methyl, ethyl, propyl, butyl, iso-propyl, ter-butyl,            e.g. methane sulfonyl (—S(O)₂CH₃); or        -   a phenyl group, unsubstituted or substituted in particular            by one or more substituents, the same or different, selected            in particular from among a halogen atom, C₁ to C₆ alkoxy            group, straight-chain or branched e.g. methoxy, ethoxy,            propoxy, iso-propoxy, butoxy, ter-butoxy; C₁ to C₅ alkyl            group, preferably C₁ to C₄, e.g. methyl, ethyl, propyl,            butyl, iso-propyl, ter-butyl;

L² representing an alkyl, straight-chain or branched, C₁ to C₅,preferably C₁ to C₄, preferably methyl, ethyl, propyl, butyl,iso-propyl, butyl, ter-butyl e.g. —CH₂—; or

-   -   an alkyl group, straight-chain or branched, C₁ to C₅, preferably        C₁ to C₄, e.g. methyl, ethyl, propyl, butyl, iso-propyl,        ter-butyl.

Preferably in the formula (I) compound, R² is:

-   -   a phenyl, unsubstituted or substituted by one or more        substituents, the same or different, selected in particular from        among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom e.g. fluorine, chlorine, bromine;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched e.g. methyl, ethyl, propyl, butyl, iso-propyl,            ter-butyl;        -   C₁ to C₅ alkyl group preferably C₁ to C₄, straight-chain or            branched, substituted in particular by one or more halogen            atoms e.g. trifluoromethyl;        -   a cyano group (—CN); or        -   an alkylsulfonyl group (—S(O)₂-alkyl) wherein the alkyl is            straight-chain or branched,

C₁ to C₅, preferably C₁ to C₄, e.g. methyl, ethyl, propyl, butyl,iso-propyl, ter-butyl, e.g. methane sulfonyl (—S(O)₂CH₃);

preferably the substituent(s) are at ortho or para position on thephenyl;

-   -   a monocylic or polycyclic heteroaryl selected from among:

-   -   unsubstituted or substituted by one or more substituents, the        same or different, selected in particular from among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom e.g. fluorine, chlorine, bromine;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched e.g. methyl, ethyl, propyl, butyl, iso-propyl,            ter-butyl;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched, substituted in particular by one or more halogen            atoms e.g. trifluoromethyl;        -   a cyano group (—CN);        -   an alkylsulfonyl group (—S(O)₂-alkyl) wherein the alkyl is            straight-chain or branched, C₁ to C₅, preferably C₁ to C₄            e.g. methyl, ethyl, propyl, butyl, iso-propyl, ter-butyl,            e.g. methane sulfonyl (—S(O)₂CH₃); or        -   a phenyl group, unsubstituted or substituted in particular            by one or more substituents, the same or different, selected            in particular from among a halogen atom, C₁ to C₆ alkoxy            group e.g. methoxy, ethoxy, propoxy, iso-propoxy, butoxy,            ter-butoxy; C₁ to C₅ alkyl group, preferably C₁ to C₄ e.g.            methyl, ethyl, propyl, butyl, iso-propyl, ter-butyl;

preferably the mono or polycyclic heteroaryl is selected from among:

-   -   -L²-carbocycle group, the carbocycle being a phenyl,        unsubstituted or substituted by one or more substituents, the        same or different, selected in particular from among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom e.g. fluorine, chlorine, bromine;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched e.g. methyl, ethyl, propyl, butyl, iso-propyl,            ter-butyl;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched, substituted in particular by one or more halogen            atoms e.g. trifluoromethyl;        -   a cyano group (—CN); or        -   an alkylsulfonyl group (—S(O)₂-alkyl) wherein the alkyl is            straight-chain or branched,

C₁ to C₅, preferably C₁ to C₄ e.g. methyl, ethyl, propyl, butyl,iso-propyl, ter-butyl, e.g. methane sulfonyl (—S(O)₂CH₃);

L² representing an alkyl, straight-chain or branched, C₁ to C₅,preferably C₁ to C₄, preferably methyl, ethyl, propyl, butyl,iso-propyl, butyl, ter-butyl e.g. —CH₂—; or

-   -   an alkyl group, straight-chain or branched, C₁ to C₅, preferably        C₁ to C₄ e.g. methyl, ethyl, propyl, butyl, iso-propyl,        ter-butyl.

Preferably, in the formula (I) compound, R² is:

-   -   a 6-membered aromatic carbocycle group, preferably phenyl        unsubstituted or substituted by one or more substituents, the        same or different, selected in particular from among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom e.g. fluorine, chlorine, bromine;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched e.g. methyl, ethyl, propyl, butyl, iso-propyl,            ter-butyl;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched substituted in particular by one or more halogen            atoms e.g. trifluoromethyl;    -   an aromatic heterocycle group with 5 or 6 members, having 1, 2        or 3 heteroatoms, the same or different, selected in particular        from among nitrogen, sulfur and oxygen, preferably pyridine        unsubstituted or substituted by one or more substituents, the        same or different, selected in particular from among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom e.g. fluorine, chlorine, bromine;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched e.g. methyl, ethyl, propyl, butyl, iso-propyl,            ter-butyl;        -   C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain or            branched, substituted in particular by one or more halogen            atoms e.g. trifluoromethyl.

Preferably in the formula (I) compound, R² is:

-   -   a phenyl group unsubstituted or substituted by one or more        substituents, the same or different, selected in particular from        among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom e.g. fluorine, chlorine, bromine;    -   a pyridine group.

Preferably, in the formula (I) compound, R³, R⁴, R⁵ and R⁶, the same ordifferent, are:

-   -   a hydrogen atom;    -   an alkyl group, straight-chain or branched, C₁ to C₅, preferably        C₁ to C₄, e.g. methyl, ethyl, propyl, butyl, iso-propyl,        ter-butyl;    -   5-, 6- or 7-member carbocycle, saturated, partly unsaturated or        aromatic, preferably saturated e.g. cyclopentyl, cyclohexyl,        substituted or unsubstituted; or

R₃ and R₄, together with the carbon atom to which they are attached,form a 5-, 6- or 7-membered carbocycle, substituted or unsubstituted,preferably saturated; e.g. cyclopentyl, cyclohexyl; or

R₅ and R₆, together with the carbon atom to which they are attached,form a 5-, 6- or 7-membered carbocycle, substituted or unsubstituted,preferably saturated; e.g. cyclopentyl, cyclohexyl.

Preferably, in the formula (I) compound R³, R⁴ each represent a hydrogenatom and R⁵ and R⁶, the same or different, represent:

-   -   a hydrogen atom;    -   an alkyl group, straight-chain or branched, C₁ to C₅, preferably        C₁ to C₄, e.g. methyl, ethyl, propyl, butyl, iso-propyl,        ter-butyl;    -   5-, 6- or 7-membered carbocycle, saturated, partly unsaturated        or aromatic, preferably saturated, e.g. cyclopentyl, cyclohexyl,        substituted or unsubstituted; or

R₃ and R₄, together with the carbon atom to which they are attached,form a 5-, 6- or 7-membered carbocycle, substituted or unsubstituted,preferably saturated; e.g. cyclopentyl, cyclohexyl; or

R₅ and R₆, together with the carbon atom to which they are attached,form a 5-, 6- or 7-membered carbocycle, substituted or unsubstituted,preferably saturated; e.g. cyclopentyl, cyclohexyl.

Preferably in the formula (I) compound R³, R⁴, R⁵ and R⁶ each representa hydrogen atom.

Preferably in the formula (I) compound n is 0.

In one particular embodiment, in the formula (I) compounds R¹ representsa group from among —C(O)CR³R⁴CR⁵R⁶C(O)OH or —(CH₂)₄C(O)OH, m, n, L¹, R²,L², R³, R⁴, R⁵, R⁶ and R⁷ having the aforementioned definitions.

Preferably, in this embodiment n is 0.

Preferably, in this embodiment m is 0.

Preferably, in this embodiment R³, R⁴, R⁵ and R⁶ each represent ahydrogen atom.

Preferably, in this embodiment R² is:

-   -   a phenyl group unsubstituted or substituted by one or more        substituents, the same or different, selected in particular from        among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom e.g. fluorine, chlorine, bromine;    -   a pyridine group.

Preferably in this embodiment n is 0, m is 0, R³, R⁴, R⁵ and R⁶ eachrepresent a hydrogen atom and R² is:

-   -   a phenyl group, unsubstituted or substituted by one or more        substituents, the same or different, selected in particular from        among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom e.g. fluorine, chlorine, bromine;    -   a pyridine group.

In one particular embodiment, in the compounds of formula (I), R¹represents a group: —C(O)CR³R⁴CR⁵R⁶C(O)OH, m, n, L¹, R², L², R³, R⁴, R⁵,R⁶ and R⁷ having the aforementioned definitions.

Preferably in this embodiment n is 0.

Preferably, in this embodiment m is 0.

Preferably, in this embodiment R³, R⁴, R⁵ and R⁶ each represent ahydrogen atom.

Preferably, in this embodiment R² is:

-   -   a phenyl group, unsubstituted or substituted by one or more        substituents, the same or different, selected in particular from        among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy; or        -   a halogen atom e.g. fluorine, chlorine, bromine.

Preferably, in this embodiment n is 0, m is 0, R³, R⁴, R⁵ and R⁶ eachrepresenting a hydrogen atom and R² is:

-   -   a phenyl group unsubstituted or substituted by one or more        substituents, the same or different, selected in particular from        among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy.

In one particular embodiment, in the formula (I) compounds, R¹represents a group: —(CH₂)₄C(O)OH, m, n, L′, R², L² and R⁷ having theaforementioned definitions.

Preferably, in this embodiment n is 0.

Preferably, in this embodiment m is 0.

Preferably, in this embodiment R² is:

-   -   a phenyl group, unsubstituted or substituted by one or more        substituents, the same or different, selected in particular from        among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom e.g. fluorine, chlorine, bromine;    -   a pyridine group.

Preferably, in this embodiment n is 0, m is 0 and R² is:

-   -   a phenyl group, unsubstituted or substituted by one or more        substituents, the same or different, selected in particular from        among:        -   C₁ to C₆ alkoxy group, preferably C₁ to C₃, straight-chain            or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,            butoxy, ter-butoxy;        -   a halogen atom e.g. fluorine, chlorine, bromine;    -   a pyridine group.

All the general and preferred characteristics of the groups R1, R2, R3,R4, R5, R6, R7, L1, L2, n and m can be combined together.

Preferably, the formula (I) compound is selected from among:

The invention also relates to compositions comprising solvates of thecompounds of formulas (I).

The compounds of formulas (I) have a carboxylic function and can besalified. They can then be in the form of addition salts with organic ormineral bases. The addition salts with bases are pharmaceuticallyacceptable salts for example such as sodium salts, potassium salts,calcium salts, which are obtained using the corresponding hydroxides ofalkaline and alkaline-earth metals as bases. As other type of additionsalts with pharmaceutically acceptable bases mention can be made ofsalts with amines and in particular glucamine, N-methylglucamine,N,N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine orlysine.

The compounds of formulas (I) can also be salified with mineral ororganic acids and preferably with pharmaceutically acceptable acids suchas hydrochloric, phosphoric, fumaric, citric, oxalic, sulfuric,ascorbic, tartaric, maleic, mandelic, methanesulfonic, lactobionic,gluconic, glucaric, succinic, sulfonic or hydroxypropanesulfonic acids.

Metformin may optionally be in the form of one of the pharmaceuticallyacceptable salts thereof. Particular can be made of the following forms:hydrochloride, acetate, benzoate, citrate, fumarate, embonate,chlorophenoxyacetate, glycolate, palmoate, aspartate, methanesulfonate,maleate, parachlorophenoxyisobutyrate, formate, lactate, succinate,sulfate, tartrate, cyclohexanecarboxylate hexanoate, octanoate,decanoate, hexadecanoate, octodecanoate, benzenesulfonate,trimethoxybenzoate, paratoluenesulfonate, adamantanecarboxylateglycoxylate, glutamate, pyrrolidonecarboxylate, naphthalene sulfonate,glucose-1-phosphate, nitrate, sulfite, dithionate, phosphate, preferablyhydrochloride, fumarate, embonate, chlorophenoxyacetate.

The salts of metformin are obtained in manner known per se by personsskilled in the art, in particular by reaction between metformin and theacids corresponding to the above-mentioned salts.

These compositions may also comprise a pharmaceutically acceptablecarrier and/or excipient.

The pharmaceutical compositions may be in any form known to thoseskilled in the art, in particular in forms intended for administrationvia parenteral, oral, rectal, per-mucosal or percutaneous route,preferably via oral route.

The compositions of the invention will be presented in the form ofsolutes or injectable suspensions or multi-dose bottles, in the form ofcoated or non-coated tablets, sugar-coated tablets, hard capsules, softcapsules, pills, tablets, powders, suppositories or rectal capsules,solutions or suspensions, for percutaneous use in a polar solvent or forpermucosal use.

The excipients suitable for such routes of administration arederivatives of cellulose of microcrystalline cellulose, alkaline-earthcarbonates, magnesium phosphate, starches, modified starches, lactosefor solid forms.

For rectal use, cocoa butter or stearates of polyethylene glycol are thepreferred excipients.

For parenteral use, water, aqueous solutes, physiological salinesolution, isotonic solutes are the carriers having most practical use.

The invention also concerns the use of a composition of the invention toprepare a medicinal product.

The invention also concerns the composition of the invention for usethereof as medicinal product.

The invention also concerns the compositions of the invention intendedfor use in the treatment of pathologies associated withinsulin-resistance syndrome (syndrome X). These pathologies areevidenced in particular in the publication by Haffner et al. (Diabetes,1992, 41(6), 715-722).

The associations of metformin with other anti-diabetic compounds lead tosaturation of response, and the actions of metformin and ofanti-diabetic compounds do not always add to one another or not alwaysin significant manner.

Most surprisingly, and advantageously, the association of metformin withthe formula (I) compounds leads to accumulation of the separate actionsof metformin and of the formula (I) compounds.

The present invention particularly concerns the pharmaceuticalcompositions of the invention for use thereof in the treatment ofpathologies associated with insulin-resistance syndrome (syndrome X).

The present invention particularly concerns a method for treatingpathologies associated with insulin-resistance syndrome, comprising theadministration of an efficient amount of a pharmaceutical composition ofthe invention to a patient in need thereof.

The present invention particularly concerns the pharmaceuticalcompositions of the invention to prepare medicinal products for thetreatment of pathologies associated with insulin-resistance syndrome.

Preferably, amongst the pathologies associated with insulin-resistancesyndrome mention can be made of diabetes and in particular Type 2diabetes.

Preferably, the compositions of the invention also allow inhibition ofneoglucogenesis.

The present invention also concerns a composition of the invention orkit comprising at least one formula (I) compound or one of the saltsthereof and metformin or a metformin salt for simultaneous, separate orsequential administration to a patient in need thereof. For simultaneousadministration, the formula (I) compound and metformin may be in amixture in the same preparation containing the same with apharmaceutically acceptable carrier or excipient. They may also bepackaged in separate preparations each with a pharmaceuticallyacceptable excipient or carrier, able to be mixed together in particularextemporaneously. For separate or sequential administration each of theactive ingredients is packaged in its own preparation containing apharmaceutically acceptable carrier or excipient.

Preferably, the composition or kit of the invention comprises metforminor one of the pharmaceutically acceptable salts thereof and a compoundselected from among:

or one of the pharmaceutically acceptable salts thereof.

In one embodiment, the composition or kit of the invention comprisesmetformin or one of the pharmaceutically acceptable salts thereof and acompound of formula:

or one of the pharmaceutically acceptable salts thereof.

Preferably, the composition or kit of the invention comprises metforminor one of the pharmaceutically acceptable salts thereof and a compoundselected from among:

or one of the pharmaceutically acceptable salts thereof.

The dosage may vary within broad limits as a function of the therapeuticindication and route of administration, and in relation to the age andweight of the subject.

The identification of the patient in need of the above-indicatedtreatment is defined by persons skilled in the art. By patient is meanta human being or an animal. A physician or veterinary surgeon is able toidentify via clinical tests, physical examination, biological assays ordiagnosis and via family and/or medical history those individuals inneed of such treatment.

By sufficient quantity is meant an amount of compound of the presentinvention that is efficient to prevent or treat pathological conditions.The sufficient quantity can be determined by those skilled in the artusing conventional techniques and observation of results obtained undersimilar circumstances. To determine the sufficient quantity, differentfactors must be taken into consideration by skilled persons, inparticular but not limited thereto: the subject, age, general state ofhealth, disease concerned and degree of seriousness; the response of thesubject, type of compound, route of administration, bioavailability ofthe administered composition, dosage, concomitant use with othermedication, etc. Preferably, in the compositions of the invention themetformin/formula (1) compound ratio is such that the metformin isadministered in an amount of 200 mg/day to 3 g/day and the compound ofthe invention is administered in an amount of 2.5 mg/day to 500 mg/day,preferably once or twice daily.

By polycarbocycle and polyheterocarbocycle according to the invention ismeant polycyclic carbocycles and heterocarbocycles, in particularcomprising two fused rings.

Preferably, and unless indicated otherwise, in the formula (I) compoundsof the invention the polycarbocycles are 9- or 10-membered and aresubstituted or unsubstituted, preferably 10-membered, are aromatic andsubstituted or unsubstituted.

Preferably, and unless indicated otherwise, in the formula (I) compoundsof the invention the polyheterocarbocycles have 9 or 10 members and maycomprise 1, 2 or 3 heteroatoms, the same or different, selected inparticular from among nitrogen, oxygen or sulfur, they are substitutedor unsubstituted, saturated, partly unsaturated or aromatic, preferablyaromatic. In particular, the polyheterocarbocycles represent

Preferably, and unless indicated otherwise, in the formula (I) compoundsof the invention the carbocycles have 5 or 6 members, are saturated,partly unsaturated or aromatic, substituted or unsubstituted, preferablythey have 6 members and are aromatic e.g. phenyl.

Preferably, and unless indicated otherwise, in the formula (I) compoundsof the invention the heterocarbocycles have 5 or 6 members and maycomprise 1, 2 or 3 heteroatoms, the same or different, selected inparticular from among nitrogen, oxygen or sulfur, they are substitutedor unsubstituted, saturated, partly unsaturated or aromatic, preferablyaromatic. For example they are selected from among

The formula (I) compounds (I) can be obtained using a process (P1)comprising:

-   -   (a) protection of the acid function (carried by R¹) of a        compound of formula (II):

-   -   where R¹ is —C(O)CR³R⁴CR⁵R⁶C(O)OH or (CH₂)₄C(O)OH;    -   (b) reaction of the compound obtained at step (a) with a        compound of formula R⁹—(CH₂)₂—R⁸ where R⁸ and R⁹, the same or        different, represent a leaving group, preferably R⁹ is more        nucleofugal than R⁸;    -   (c) reaction of the compound obtained at step (c) with a        compound of formula (III)

-   -   where L¹, n, m, R² and R⁷ have the definitions given for formula        (I);    -   (d) deprotection of the compound obtained at step (c).

The starting products are commercially available or can be easilyprepared by persons skilled in the art on the basis of their generalknowledge of organic chemistry.

The compounds for which R¹ represents C(OH)(H)CR³R⁴CR⁵R⁶C(O)OH can beobtained by reducing compounds for which R¹ representsC(O)CR³R⁴CR⁵R⁶C(O)OH. This reduction can be implemented for example inthe presence of NaBH₄ in ethanol. This reduction can be performed forexample between steps (b) and (c).

The compounds for which R¹ represents

can be obtained by:

-   -   lactonization of the compounds for which R¹ represents        —C(OH)(H)CR³R⁴CR⁵R⁶C(O)OH. This lactonization is conducted for        example before step (c); or    -   lactonization of the compounds for which R¹ represents        —C(O)CR³R⁴CR⁵R⁶C(O)OH. This lactonization is conducted for        example after step (d).

These lactonizations can be performed using any method known to skilledpersons, for example they can be performed in the presence of CF₃CO₂H indichloromethane.

Step (a), corresponding to protection of the acid function, can beconducted in any manner known to skilled persons provided thatprotection is selective for the acid function in relation to the alcoholfunction. Among the protective groups of the carboxylic function, thosegenerally described in Protective Groups in Organic Synthesis, Greene T.W. and Wuts P. G. M, published by John Wiley and Sons, 1991 and inProtective Groups, Kocienski P. J., 1994, Georg Thieme Verlag, aresuitable. For example, it can be envisaged to protect the carboxylicfunction in ester form (C₁-C₆ alkyl, e.g. methyl). For example, step (a)can be performed by reaction of the formula (I) compound with methanolin the presence of an acid, sulfuric acid in particular.

Step (b) is preferably performed in an aprotic polar solvent such asacetonitrile, dimethylformamide (DMF), acetone, dimethylsulfoxide andhalogenated hydrocarbons such as dichloromethane or dichloroethane, at asuitable temperature, in particular between 15 and 80° C., preferablybetween 15 and 35° C. One preferred solvent in particular isacetonitrile. Advantageously, this step takes place in the presence of abase such as potassium carbonate. Persons skilled in the art know that aleaving group is all the more labile the more the corresponding anionicspecies is stable. Therefore if R⁹ is more nucleofugal than R⁸ thiscorresponds to the fact that R⁹⁻ is more stable than R⁸⁻. The leavinggroups R⁸ and R⁹, the same or different, are selected from among halogenatoms, preferably chlorine and bromine; (C₆-C₁₀) arylsulfonyloxy groups,the aryl group optionally being substituted by one or more C₁ to C₆alkyl groups; (C₁-C₆) alkylsulfonyloxy groups wherein the alkyl group isoptionally substituted by one or more halogen atoms. Preferably R⁸ ischlorine and R⁹ is bromine.

Step (c) is a nucleophilic substitution step for which the operatingconditions can easily bedetermined by those skilled in the art.Advantageously the reaction is implemented in an aprotic polar solventin the presence of a base. Examples of suitable solvents areacetonitrile, dimethylformamide, acetone, dimethylsulfoxide andhalogenated hydrocarbons such as dichloromethane or dichloroethane. Asbase, mention can be made of carbonates of alkaline or alkaline-earthmetals e.g. potassium carbonate. Advantageously the reaction at step (c)is conducted at a temperature of 50 to 120° C., for example under refluxof the solvent in the presence of an iodide of an alkaline metal such aspotassium iodide. The amount of alkaline iodide may be variable andessentially depends on the type of reagents, type of solvent andreaction temperature. The reaction is generally stoichiometric, it isnonetheless possible to operate with a slight excess of one or other ofthe reagents.

The deprotection step (d) may be any deprotection known to personsskilled in the art and compatible with the protection implemented atstep (a) allowing recovery of the acid function. For example, it mayinvolve saponification in a basic, acid or catalytic (Pd/C) medium.

The formula (I) compounds can also be obtained using a second process(P2) comprising:

(i) reaction of a formula (III) compound with a compound of formulaR⁹—(CH₂)₂—R⁸ where R⁸ and R⁹ are such as defined in process (P1);

-   -   (ii) protection of the acid function of a formula (II) compound;    -   (iii) reaction between the compound obtained at step (i) and the        compound obtained at step (ii);    -   (iv) deprotection of the compound obtained at step (iii).

The starting products are commercially available or can easily beprepared by persons skilled in the art on the basis of their generalknowledge of organic chemistry.

The compounds for which R¹ represents C(OH)(H)CR³R⁴CR⁵R⁶C(O)OH can beobtained by reducing compounds for which R¹ represents—C(O)CR³R⁴CR⁵R⁶C(O)OH. This reduction can be performed for example inthe presence of NaBH₄ in ethanol. This reduction can be conducted forexample between steps (ii) and (iii).

The compounds for which R¹ represents

can be obtained by:

-   -   lactonization of the compounds for which R¹ represents        —C(OH)(H)CR³R⁴CR⁵R⁶C(O)OH. This lactonization can take place for        example before step (iii); or    -   lactonization of the compounds for which R¹ represents        —C(O)CR³R⁴CR⁵R⁶C(O)OH. This lactonization can be performed for        example after step (iv).

These lactonizations can be performed using any method known to personsskilled in the art, for example they can be performed in the presence ofCF₃CO₂H in dichloromethane.

An equilibrium generally exists between the forms for which R¹represents —C(OH)(H)CR³R⁴CR⁵R⁶C(O)OH and the forms for which R¹represents

Step (i) is preferably implemented in an aprotic polar solvent such asacetonitrile, dimethylformamide (DMF), acetone, dimethylsulfoxide andhalogenated hydrocarbons such as dichloromethane or dichloroethane, atan adapted temperature in particular between 15 and 80° C., preferablybetween 15 and 35° C. One preferred solvent in particular isacetonitrile. Advantageously, this step is conducted in the presence ofa base such as potassium carbonate.

Step (ii), corresponding to protection of the acid function, can beconducted in any manner known to persons skilled in the art, providedthat protection is selective for the acid function in relation to thealcohol function. Amongst the protective groups of the carboxylicfunction those generally described in Protective Groups in OrganicSynthesis, Greene T. W. and Wuts P. G. M, published by John Wiley andSons, 1991 and in Protective Groups, Kocienski P. J., 1994, Georg ThiemeVerlag, are suitable. For example, the protection of the carboxylicfunction can be envisaged in ester form (C₁-C₆ alkyl e.g. methyl). Forexample step (a) can be conducted by reaction of the formula (I)compound with methanol in the presence of an acid, sulfuric acid inparticular.

Step (iii) is a nucleophilic substitution step for which the operatingconditions can easily be determined by those skilled in the art.Advantageously, the reaction is conducted in an aprotic polar solvent inthe presence of a base. Examples of suitable solvents are acetonitrile,dimethylformamide, acetone, dimethylsulfoxide and halogenatedhydrocarbons such as dichloromethane or dichloroethane. As base, mentioncan be made of carbonates of alkaline or alkaline-earth metals such aspotassium carbonate. Advantageously the reaction at step (c) isconducted at a temperature of 50 to 120° C., for example under reflux ofthe solvent in the presence of an iodide of an alkaline metal such aspotassium iodide. The amount of alkaline iodide may be variable and isessentially dependent on the type of reagents, the type of solvent andreaction temperature. The reaction is generally stoichiometric, but itis nevertheless possible to operate with a slight excess of one or otherof the reagents.

The deprotection step iv) can be any deprotection known to personsskilled in the art and compatible with the protection performed at step(ii) allowing recovery of the acid function. For example it may besaponification in a basic, acid or catalytic (Pd/C) medium.

Advantageously, the formula (I) compounds of the invention actconcomitantly on 3 target organs:

-   -   the liver via inhibition of hepatic gluconeogenesis (or        neoglucogenesis);    -   skeletal muscle via stimulation of the glucose consumption        thereof; and    -   the pancreas via stimulation of insulin secretion by beta cells.        Therefore the formula (I) compounds have the potential to        correct the 3 major deficiencies observed in patients suffering        from Type 2 diabetes.

The mechanism of action of the formula (I) compounds differs from thatof metformin which allows a greater effect to be obtained from theassociation of the formula (I) compound+metformin than the effectobtained from metformin alone.

On the basis of these data and of the methods described below, personsskilled in the art, without any difficulty, will be able to confirm theadditive effect of any formula (1) compound or more broadly to selectany molecule able to be associated with metformin.

The present invention also concerns a method to select a compound fortreating pathologies associated with insulin-resistance syndrome whichprovides an additional effect to the effect of metformin, comprising thesteps of:

-   -   a) providing fasting, normal animals;    -   b) measuring glycaemia in these animals;    -   c) administering the compound to be tested to one portion of the        animals, metformin to a second portion of the animals and an        association of metformin and the compound to be tested to a last        portion of the animals;    -   d) administering a glucose load to the animals, in particular of        2 to 4 g/kg animal body weight;    -   e) measuring glycaemia at different times;    -   f) determining whether the compound has an additive effect in        addition to the effect of metformin on lowering of glycaemia, in        particular comparing the glycaemia area under curve obtained for        each of the compounds administered and determining whether the        tested compound in association with metformin allowed a        reduction in the glycaemia area under curve compared with        metformin administered alone.

The method comprises a step g) to select the compound if it gives apositive response at step f).

The method may also comprise steps b), d) and e) conducted in batches ofcontrol animals that are not given any compound.

Preferably, the animals are normal, fasting mice, preferably Swiss micee.g. 8-week old Swiss mice that have been fasting for 17 h inparticular.

Preferably the administration of the compounds is given via oral route.

Preferably the glucose load is given via oral route.

Typically glycaemia is measured using a glucometer and glycaemia teststrips.

Preferably the amount used of compound to be tested is between 1 and 200mg/kg animal body weight.

Preferably, the amount of metformin used is between 300 mg/kg and 1000mg/kg animal body weight.

Preferably, the association of metformin+compound to be tested comprises300 to 1000 mg/kg animal body weight of metformin and 1 to 200 mg/kganimal body weight of compound to be tested.

According to one test condition the compound to be tested is or is not aformula (I) compound.

The selection method of the present invention may also comprise theprior steps of:

-   -   1) determining the toxicity of the compound to be tested;    -   2) providing liver cells of fasting animals;    -   3) incubating these cells with lactate or glutamine;    -   4) adding the compound to be tested to the incubation medium;    -   5) performing enzymatic assay of lactate or glutamine        consumption and/or of glucose production and/or assay of ATP        cell concentration;    -   6) determining which compounds are not or scarcely toxic        allowing stimulation of complete oxidation of the lactate or        glutamine and/or reduction of ATP cell concentration; and/or    -   7) providing animals having Type 2 diabetes;

8) administering the compound to be tested to these animals;

-   -   9) administering a glucose load in particular of 1 to 3 g/kg        animal body weight;    -   10) evaluating the peripheral consumption of glucose by skeletal        muscle and/or the concentration of circulating insulin;    -   11) determining which toxic or scarcely toxic compounds allow an        increase in glucose consumption in the muscle and/or an increase        in the concentration of circulating insulin.

The method may also comprise steps 3) and 5) and/or steps 9) and 10)conducted in batches of control animals not given any compound.

Preferably, administration of the compounds is via oral route.

Preferably, the glucose load is given via oral route.

Preferably, the cells at step 1) are liver cells of fasting rats,preferably fasting for 48 h.

Preferably, incubation is performed in the presence of 0.5 to 5 mM oflactate or glutamine.

Preferably, the compound to be tested is added in an amount of 0.5 to 2mM.

The enzymatic assays of lactate or glutamine consumption, of glucoseproduction and assay of ATP cell concentration are performed usingmethods well known to persons skilled in the art and in particular thosedescribed by Bergmeyer 1974.

Preferably the lactate used is 2-¹³C-lactate which allows bettermonitoring of its complete oxidation, in particular using carbon-13spectroscopy.

The method of the invention then comprises either the implementation ofsteps 1) to 6) followed by implementation of steps a) to f) on thosecompounds responding positively at step 6), or the implementation ofsteps 7) to 11) followed by implementation of steps a) to f) on thosecompounds responding positively at step 11), or even the implementationof steps 1) to 11) followed by implementation of steps a) to f) on thosecompounds responding positively at steps 6) and 11).

The present invention also concerns a method to select non-toxic orscarcely toxic compounds allowing stimulation of complete lactate orglutamine oxidation and/or a reduction in ATP cell concentration,comprising the following steps of:

-   -   1) determining the toxicity of the compound to be tested;    -   2) providing liver cells of fasting animals;    -   3) incubating these cells with lactate or glutamine;    -   4) adding the compound to be tested to the incubation medium;    -   5) performing enzymatic assay of lactate or glutamine        consumption and/or of glucose production and/or assay of ATP        cell concentration;    -   6) determining those compounds that are not or scarcely toxic        allowing stimulation of complete lactate or glutamine oxidation        and/or a reduction in ATP cell concentration.

The method may also comprise steps 3) and 5) conducted in batches ofcontrol animals not given any compound.

The method comprises a step 7) to select the compound if it respondspositively at step 6).

The present invention also concerns a method to select non-toxic orscarcely toxic compounds allowing an increase in glucose consumption bymuscle and/or an increase in the concentration of circulating insulin,comprising the steps of:

-   -   1) determining the toxicity of the compound to be tested;    -   2) providing animals having Type 2 diabetes;    -   3) administering the compound to be tested to these animals;    -   4) administering a glucose load to the animals in particular of        1 to 3 g/kg animal body weight;    -   5) evaluating the peripheral consumption of glucose by skeletal        muscle and/or the concentration of circulating insulin;    -   6) determining the non-toxic or scarcely toxic compounds        allowing an increase in glucose consumption by muscle and/or an        increase in the concentration of circulating insulin.

The method may also comprise steps 4) and 5) conducted in batches ofcontrol animals not given any compound.

The method comprises a step 7) to select the compound if it respondspositively at step 6).

The present invention also concerns a method to select non-toxic orscarcely toxic compounds which allow stimulation of complete lactate orglutamine oxidation, a reduction in ATP cell concentration, an increasein glucose consumption by muscle and an increase in the concentration ofcirculating insulin, comprising the following steps of:

-   -   1) determining the toxicity of the compound to be tested;    -   2) providing liver cells of fasting animals;    -   3) incubating these cells with lactate or glutamine;    -   4) adding the compound to be tested to the culture medium    -   5) performing enzymatic assay of lactate or glutamine        consumption and assay of ATP cell concentration;    -   6) determining the compounds that are not or scarcely toxic        allowing stimulation of complete lactate or glutamine oxidation        without increasing the ATP cell concentration; and    -   7) providing animals having Type 2 diabetes;    -   8) administering the compound to be tested to these animals;    -   9) administering a glucose load to the animals, in particular of        1 to 3 g/kg animal body weight;    -   10) evaluating the peripheral consumption of glucose by skeletal        muscle and the concentration of circulating insulin;    -   11) determining those non-toxic or scarcely toxic compounds        allowing an increase in glucose consumption by muscle and an        increase in the concentration of circulating insulin.

The method may also comprise steps 3), 5), 9) and 10) conducted inbatches of control animals not given any compound.

The method comprises a step 12) to select the compound if it respondspositively at step 11).

The present invention also concerns a method for producing a compositioncomprising in association metformin or a salt of metformin and at leastone compound having an additive effect adding to the effect ofmetformin, for example a formula (I) compound, the enantiomers,diastereoisomers and pharmaceutically acceptable salts thereof, whereinthere is associated with metformin a compound having respondedpositively to the selection method just described, in its differentconfigurations, or else the compound is subjected to this selectionmethod, and if the compound proves to have a positive response to thetest it is retained for the composition. This production method maycomprise the association of the compound and of metformin in one samecomposition or in two separate compositions to be administered to thesame patient, for example associated in a kit.

The present invention is now described with the help of non-limitingexamples.

EXAMPLE 1 General Scheme for Preparing Compounds in which R¹ RepresentsC(O)CR³R⁴CR⁵R⁶C(O)OH

The first step is a demethylation step which can be performed byreacting HBr in an acetic acid medium.

The second step is an esterification reaction which can be performed byreaction with methanol in the presence of sulphuric acid.

Steps 3 and 4 are nucleophilic substitution steps.

Step 5 can be conducted in particular via acid hydrolysis orsaponification.

Step 1: Demethylation

Equipment: 1 L Round-Bottomed Flask Equipped with Magnetic Agitation andCoolant—Oil Bath.

4-(4-methoxyphenyl)-4-oxobutanone 1 (40 g) is placed in solution inacetic acid (360 ml) and 48% aqueous hydrobromic acid (120 ml). Thereaction medium is heated to 130° C. overnight.

The progress of the reaction is monitored by TLC (eluting withheptane/ethyl acetate 1:1). After overnight agitation under theseconditions, the starting ether 1 is seen to disappear to the benefit ofa more polar product.

The reaction medium is concentrated to dryness under reduced pressure.The residue obtained is re-dissolved in water and the aqueous phaseextracted three times with ethyl acetate. Once combined, the organicphases are washed once with saturated sodium chloride solution, driedover magnesium sulfate, filtered and concentrated under reduced pressureto afford a solid (38 g).

^(1H)NMR analysis of the reaction mixture reveals the presence of theexpected phenol 2 in a mixture with about 6% of starting ether.

Quantitative yield.

Step 2: Esterification

Equipment: 1 L Three-Necked Flask Equipped with Magnetic Agitation,Coolant and Placed Under a Stream of Nitrogen—Oil Bath.

The derivative 4-(4-hydroxyphenyl)-4-oxobutanoic acid 2 (48 g) is placedin solution in methanol (480 ml) before slow pouring of sulfuric acid(48 ml). The solution obtained is heated to 70° C. overnight.

The progress of the reaction is monitored by TLC (eluting withheptane/ethyl acetate 1:1). After overnight agitation under theseconditions, the starting acid 2 is seen to disappear to the benefit of aless polar product.

The reaction medium is concentrated to dryness under reduced pressure.The residue obtained is re-dissolved in water (500 ml) anddichloromethane (500 ml). The heterogeneous medium is carefullyneutralised with a saturated solution of sodium hydrogen carbonate (pH7-8). The aqueous phase is then extracted three times with ethylacetate. Once combined, the organic phases are washed with saturatedsodium chloride solution, dried over magnesium sulfate, filtered andconcentrated under reduced pressure to afford a solid (49.6 g).

^(1H)NMR analysis of the reaction mixture reveals the presence of theexpected ester 3 in a mixture with less than 3% of the compound methyl4-(4-methoxyphenyl)-4-oxobutanoate.

Yield: 96%.

Step 3: Nucleophilic Substitution

Equipment: 1 L Three-Necked Flask Equipped with Magnetic Agitation,Coolant and Placed Under a Stream of Nitrogen—Oil Bath.

The methyl 4-(4-hydroxyphenyl)-4-oxobutanoate 3 (49.6 g) is placed insolution in acetonitrile (400 ml). Potassium carbonate (98.77 g) isadded to the solution. The reaction medium is heated to 50° C. beforepouring a solution of 1-bromo-2-chloroethane (102.5 g) in acetonitrile(170 ml). The reaction medium is heated to 80° C. overnight.

The progress of the reaction is monitored by TLC (eluting withheptane/ethyl acetate 7:3). After an agitation time of 24 h under theseconditions compound 3 is seen to disappear to the benefit of a lesspolar product.

After return to ambient temperature, the reaction medium is filtered toremove the potassium carbonate. The potassium carbonate is rinsed withacetonitrile and the filtrate is concentrated to dryness under reducedpressure. The residue obtained is re-dissolved in water (500 ml) and theaqueous phase is extracted twice with ethyl acetate (600 ml). Theorganic phases are combined, washed once with 1M sodium hydroxidesolution (400 ml), dried over magnesium sulfate, filtered andconcentrated under reduced pressure to afford a beige solid (61.44 g).

^(1H)NMR analysis of the reaction mixture reveals the presence of theexpected chlorinated derivative 4.

Yield: 95%.

Step 4: Nucleophilic Substitution

Equipment: Stem Apparatus Equipped with Heating System and OrbitalAgitation, 9 ml Reactors—Manifold—Multivac Evaporation System—AllexisExtraction Apparatus

Under a stream of nitrogen, the chlorinated derivative 4 (500 mg, 1.85mmol, 1 eq.) is distributed over the different reactors and placed insolution in acetonitrile (5 ml) in the presence of R-piperazine (1.85mmol, 1 eq.), previously dried potassium carbonate (766 mg, 5.54 mmol, 3eq.), potassium iodide (307 mg, 1.85 mmol, 1 eq.). After passing astream of nitrogen the reactors are closed and heated to 80° C.

After 72 hours heating is halted. On return to ambient temperature thedifferent reaction media are filtered in parallel on Supelco cartridgesconnected to a Manifold to remove the inorganic salts. After rinsingwith acetonitrile, the filtrates are concentrated to dryness underreduced pressure using the Multivac. The residues obtained arere-dissolved in water (20 ml) and extracted three times in parallel onthe Allexis apparatus with ethyl acetate (10 ml). The different organicphases are combined, dried over magnesium sulfate, filtered andconcentrated under reduced pressure using the Multivac.

The different reaction mixtures are purified on a pre-packed Redisep 40g chromatography column, Biotage SP4 system, using adichloromethane/methanol gradient.

Step 5: Acid Hydrolysis

Equipment: Syncore—Heating System—Orbital Agitation—50 ml Reactors

The different esters are placed in solution in hydrochloric acid 5 andthe solutions heated to 90° C. for 2 hours. TLC monitoring (eluting withdichloromethane/methanol 98:2, UV detection) of the reaction medium ineach reactor allows verification that the esters have disappeared to thebenefit of more polar products.

The reaction media are concentrated to dryness under reduced pressure inthe Multivac. The solids obtained are triturated with acetone (10V) thenfiltered through a sintered filter and dried in vacuo.

Step 5: Saponification

Equipment: Radley Equipped with Reactors and Magnetic Agitation.

The different esters are placed in solution in methanol (4V) in thepresence of 1M sodium hydroxide solution (8V). After overnight agitationunder these conditions TLC monitoring (eluting withdichloromethane/methanol 98:2, UV detection) allows verification of thedisappearance of the esters to the benefit of more polar products.

After concentration of the methanol, the different aqueous solutions areextracted with ethyl acetate (5 ml) and acidified to pH 1 with 3Mhydrochloric acid solution.

The acids are then isolated via desalination by eluting the differentaqueous solutions on Porapak Rxn resin.

Desalination protocol:

-   -   Condition the resin with 45 ml methanol    -   Deposit the aqueous phase (4 to 5 ml)    -   Rinse with 100 ml methanol    -   Elute with 100 ml of 2M ammonia solution in methanol    -   Concentrate to dryness under reduced pressure.

The solids obtained after desalination are triturated with ethyl etheror recrystallized in acetonitrile.

The following compounds were obtained by implementing the general schemeof Example 1 (Step 5 acid hydrolysis).

Yield: 95% Structure: Compound 1

Molecular weight: Molecular formula: Form/colour: 473.38 C₂₂H₂₇Cl₂FN₂O₄White solid ^(1H)NMR (DMSO, 300 MHz, δ ppm): 2.56 (t, 2H); 3.18-3.41 (m,6H); 3.50 (d, 2H); 3.63-3.70 (m, 4H); 4.59 (t, 2H); 7.00-7.23 (m, 6H);7.99 (d, 2H); 11.49 (broad s, 1H) MS (ESI): 401.10 (MH⁺); 399.2 (MH⁻)base form Yield: 93% Structure: Compound 2

Molecular weight: Molecular formula: Form/colour: 456.37 C₂₁H₂₇Cl₂N₃O₄White solid ^(1H)NMR (DMSO, 300 MHz, δ ppm) : 2.56 (t, 2H); 3.18-3.32(m, 4H); 3.42-3.52 (m, 2H); 3.62-3.72 (m, 4H); 4.45 (d, 2H); 4.55 (t,2H); 6.88 (t, 1H); 7.12-7.18 (m, 3H); 7.80-7.85 (m, 1H); 8.00 (d, 2H);8.14 (d, 1H); 11.24 (broad s, 1H) MS (ESI): 384.30 (MH⁺); 382.20 (MH⁻)base form Yield: 99% Structure: Compound 3

Molecular weight: Molecular formula: Form/colour: 485.41 C₂₃H₃₀Cl₂N₂O₅White solid ^(1H)NMR (DMSO, 300 MHz, δ ppm): 2.56 (t, 2H); 3.12-3.33 (m,6H); 3.61-3.67 (m, 4H); 3.73 (s, 3H); 3.84 (d, 2H); 4.57 (t, 2H); 6.45(dd, 1H); 6.53 (s, 1H); 6.58 (dd, 1H); 7.10-7.19 (m, 3H); 8.00 (d, 2H);11.21 (broad s, 1H) MS (ESI): 413.20 (MH⁺); 411.20 (MH⁻) base form

EXAMPLE 2 General Scheme for the Preparation of Compounds Wherein R¹Represents —(CH₂)₄C(O)OH

Step 1 is an esterification reaction, steps 2 and 3 are nucleophilicsubstitution reactions and step 4 is a hydrolysis reaction.

Step 1: Esterification

Equipment: 500 ml Three-Necked Flask Equipped with Magnetic Agitation,Coolant and Placed Under a Stream of Nitrogen—Oil Bath.

5-(4-hydroxyphenyl)-pentanoic acid 1 (25 g) is placed in solution inmethanol (37 5 ml) before slow pouring of sulfuric acid (25 ml). Thesolution obtained is heated to 65° C. overnight. The progress of thereaction is monitored by TLC (eluting with heptane/ethyl Acetate 1:1).After overnight agitation under these conditions the starting acid 1 isseen to disappear to the benefit of a less polar product.

The reaction medium is concentrated to dryness under reduced pressure.The residue obtained is re-dissolved in dichloromethane (300 ml). Theheterogeneous medium is neutralised and basified with precaution withsaturated sodium hydrogen carbonate solution (pH 8-9). The aqueous phaseis then extracted three times with dichloromethane. Once combined, theorganic phases are washed once with saturated sodium chloride solution,dried over magnesium sulfate, filtered and concentrated under reducedpressure to afford a pinkish oil (27 g).

Yield: 99%

Step 2: Nucleophilic Substitution

Equipment: 500 ml Three-Necked Flask Equipped with Magnetic Agitation,Coolant and Placed Under a Stream of Nitrogen—Oil Bath.

The ester methyl 5-(4-hydroxyphenyl)-pentanoate 2 (26.8 g) is placed insolution in acetonitrile (250 ml). Previously dried potassium carbonate(53.36 g) is added to the solution. The reaction medium is heated to 50°C. before slow pouring of a solution of 1-bromo-2-chloroethane (55.36 g)in acetonitrile (60 ml). The reaction medium is heated to 80° C.overnight.

The progress of the reaction is monitored by TLC (eluting withheptane/ethyl Acetate 7:3). After an agitation time of 24 h under theseconditions the presence of phenol 2 is still observed. An additionalquantity of 1-bromo-2-chloroethane (9.23 g, 64.3 mmol, 0.5 eq.) is addedand the reaction medium is held under agitation at 80° C. for a further24 h. TLC monitoring shows that the reaction does not change. NMR of theproton of an aliquot of the reaction medium allows quantification of thecompounds 2 and 3 in a ratio of the order of 33:66.

On return to ambient temperature, the reaction medium is filtered toremove the potassium carbonate. The potassium carbonate is rinsed withethyl acetate and the filtrate is concentrated to dryness under reducedpressure. The residue obtained is re-dissolved in water (100 ml) and theaqueous phase is extracted three times with ethyl acetate (100 ml). Theorganic phases are combined, washed with 1M sodium hydroxide solution(200 ml) then with water (100 ml), dried over magnesium sulfate,filtered and concentrated under reduced pressure to afford a beige oil(39.5 g).

^(1H)NMR analysis of the reaction mixture reveals the presence of theexpected chlorinated derivative 3 in a mixture with close to 30% of rawmaterial 2.

The reaction mixture is purified by chromatography on silica gel (1 L).The compounds to be separated are eluted using a heptane/ethyl acetategradient.

The desired compound is isolated in oil form (22.4 g).

Yield: 64%

Step 3: Nucleophilic Substitution

Equipment: Stem Apparatus Equipped with Heating System and OrbitalAgitation. 9 ml Reactors—Manifold—Multivac Evaporation System—AllexisExtraction Apparatus

Under a stream of nitrogen, the chlorinated derivative 3 (500 mg, 1.85mmol, 1 eq.) is distributed over the different reactors and placed insolution in acetonitrile (5 ml) in the presence of R-piperazine (1.85mmol, 1 eq.), previously dried potassium carbonate (766 mg, 5.54 mmol, 3eq.) and potassium iodide (307 mg, 1.85 mmol, 1 eq.). After passing astream of nitrogen the reactors are closed and heated to 80° C.

After 72 hours the heating is halted. On return to ambient temperaturethe different reaction media are filtered in parallel on Supelcocartridges connected to a Manifold to remove the inorganic salts. Afterrinsing with acetonitrile the filtrates are concentrated to drynessunder reduced pressure using the Multivac. The residues obtained arere-dissolved in water (20 ml) and extracted three times in parallel onAllexis apparatus with ethyl acetate (10 ml). The different organicphases are combined, dried over magnesium sulfate and concentrated underreduced pressure using the Multivac.

The different reaction mixtures are purified by chromatography on apre-packed Redisep 40 g column, Biotage SP4 system, using adichloromethane/methanol gradient.

Step 4: Hydrolysis

Equipment: Stem Apparatus Equipped with Heating System and OrbitalAgitation. 9 ml Reactors—Multivac Evaporation System.

The different esters derived from 3 are placed in solution indichloromethane (5 ml) in the presence of potassium trimethylsilanoate.The reaction medium is heated to 35° C. overnight. After overnightagitation under these conditions, TLC monitoring (eluting withdichloromethane/methanol 98:2, UV detection) allows verification thatthe esters have disappeared to the benefit of more polar products.

The different reaction media are concentrated to dryness under reducedpressure. The residues obtained are triturated with a mixture of diethylether (4 volumes) and ethanol (2 volumes) to remove excess potassiumtrimethylsilanoate and residual trimethylmethoxysilane. Afterfiltration, the potassium carboxylates are isolated and dried underreduced pressure.

Each potassium carboxylate is placed in solution in a minimum amount ofdistilled water (1 to 11 ml) before adding 1N hydrochloric acid solution(2 eq.). After an agitation time of 30 minutes, the acids obtainedprecipitate in the form of a gum. Each acid is regularly triturateduntil the onset of a powdery precipitate. The precipitates are filtered,washed once with water then dried under reduced pressure in the presenceof P₂O₅.

The following compounds were obtained by implementing the general schemeof Example 2

Yield: 85% Structure:

Compound 4 Molecular weight: Molecular formula: Form/colour:   448.99C₂₄H₃₃ClN₂O₄ White solid ppm) ^(1H)NMR (MeOD, 300 MHz, δ: 1.47-1.59 (m,4H); 2.23 (t, 2H); 2.53 (t, 2H); 3.19-3.62 (m, 10H); 3.80 (s, 3H); 4.33(t, 2H); 6.84-7.04 (m, 6H); 7.09 (d, 2H) MS (ESI): 413.20 (MH⁺); 411.20(MH⁻)

EXAMPLE 3 Study on the Additive Anti-Diabetic Action in Swiss MiceBetween Metformin and Various Compounds in the Metabolys Portfolio

The anti-diabetic action of the compounds in Examples 1 and 2 weredetermined via oral route in normal Swiss mice fasting for 17 hours.

The mice used were aged 8 weeks. The animals were housed for a minimumtime of one week after delivery (ordered from Charles River France) upuntil the day of experimentation in an animal facility at a temperatureregulated at 21-22° C. and subjected to a light cycle (from 9 h to 17 h)and dark cycle (from 19 h to 7 h). They were fed a maintenance diet:water and food were provided

ad libitum

.

The animals were treated via oral route 1 hour before oraladministration of a glucose load (oral glucose tolerance test —OGTT).Glycaemia was measured at various times before and after this glucoseload. This glycaemia was measured using a glucometer (Lifescan OneTouchUltra, Lifescan, Johnson and Johnson Company) and OneTouch Ultraglycaemia test strips.

In the Tables below n represents the number of mice included in thestudy.

-   -   1. Study on the additive effect of compound 1 (50 mg/kg per os)        adding to the effect of metformin (300 mg/kg per os) on changes        in glycaemia levels after an oral glucose load (OGTT) in Swiss        mice fasting for 17 hours.

TABLE 1 Additive effect of compound 1 with metformin on glycaemia(mM/litre) in Swiss mice fasting for 17 h during a glucose tolerancetest. Glycaemia Experimental Time (mn) conditions −60 0 30 60 90 120Carrier (n = 5) 4.4 ± 0.3 4.8 ± 0.4 19.5 ± 1.2 15.1 ± 1.5 10.1 ± 0.9 7.8± 0.8 Compound 1 5.0 ± 0.2 4.5 ± 0.3 15.2 ± 1.9 10.6 ± 0.2  6.5 ± 0.55.3 ± 0.2 (50 mg/kg) (n = 5) Metformin 3.7 ± 0.3 3.2 ± 0.3  8.6 ± 0.5 9.4 ± 0.8  7.7 ± 1.0 6.2 ± 0.8 (300 mg/kg) (n = 5) Compound 1 3.9 ± 0.23.0 ± 0.3  7.8 ± 1.0  4.5 ± 0.8  3.8 ± 0.6 2.6 ± 0.6 (50 mg/kg) +Metformin (300 mg/kg ) (n = 5)

The 2 compounds were administered successively one hour before theglucose load. All the groups were composed of 5 mice (metformin alone,compound 1 alone, metformin+compound 1, control group with the carrieralone). Blood samples were taken at 0, 30, 60, 90 and 120 minutes afterthe glucose load.

After administration of the glucose load, metformin alone caused theglycaemia area under curve to drop by 44.2%, compound 1 alone by 42.5%and the metformin plus compound combination by 79.5%.

These results show a major effect of the compositions of the inventionon changes in glycaemia.

-   -   2. Study on the additive effect of compound 2 (50 mg/kg per os)        adding to the effect of metformin (300 mg/kg per os) on changes        in glycaemia levels after an oral glucose load (OGTT) in Swiss        mice fasting for 17 hours.

TABLE 2 Additive effect of compound 2 with metformin on glycaemia(mM/litre) in Swiss mice fasting for 17 h during a glucose tolerancetest. Glycaemia Experimental Time (mn) conditions −60 0 30 60 90 120Carrier (n = 4) 4.4 ± 0.2 5.2 ± 0.4 19.6 ± 2.9 18.7 ± 2.9 9.3 ± 1.2 7.1± 0.6 Compound 2 4.6 ± 0.4 4.9 ± 0.2 14.5 ± 1.4 10.4 ± 0.5 8.3 ± 1.1 6.8± 0.6 (50 mg/kg) (n = 4) Metformin 3.8 ± 0.1 3.6 ± 0.3 11.2 ± 0.3  9.5 ±0.4 8.0 ± 1.3 8.2 ± 0.7 (300 mg/kg) (n = 4) Compound 2 4.5 ± 0.5 3.8 ±0.3  7.3 ± 1.8  5.9 ± 1.8 4.9 ± 1.3 4.1 ± 0.7 (50 mg/kg) + Metformin(300 mg/kg) (n = 4)

The 2 compounds were administered successively one hour before theglucose load. All the groups were composed of 4 mice (metformin alone,compound 2 alone, metformin+compound 2, control group with carrieralone). Blood samples were taken at 0, 30, 60, 90 and 120 minutes afterthe glucose load.

After the glucose load, metformin alone caused the glycaemia area undercurve to drop by 38.7%, compound 2 by 40.5% and the combination ofmetformin plus compound 2 by 76.8%.

These results show a major effect of the compositions of the inventionon changes in glycaemia.

-   -   3. Study on the additive effect of compound 3 (50 mg/kg per os)        adding to the effect of metformin (300 mg/kg per os) on changes        in glycaemia levels after an oral glucose load (OGTT) in Swiss        mice fasting for 17 hours.

TABLE 3 Additive effect of compound 3 with metformin on glycaemia(mM/litre) in Swiss mice fasting for 17 h during a glucose tolerancetest. Glycaemia Experimental Time (mn) condition −60 0 30 60 90 120Carrier (n = 4) 4.7 ± 0.4 5.4 ± 0.3 17.2 ± 2.1 15.4 ± 2.1 10.5 ± 1.4 8.3± 0.7 Compound 3 4.4 ± 0.3 5.5 ± 0.3 11.3 ± 0.6  9.7 ± 0.4  7.4 ± 0.37.2 ± 0.5 (50 mg/kg) (n = 4) Metformin 5.6 ± 0.3 6.0 ± 0.3  9.2 ± 0.8 8.2 ± 0.4  7.7 ± 0.2 9.6 ± 0.8 (300 mg/kg) (n = 4) Compound 3 5.4 ± 0.45.4 ± 0.3  8.4 ± 0.7  7.7 ± 0.7  7.0 ± 1.5 6.5 ± 1.2 (50 mg/kg) +Metformin (300 mg/kg) (n = 4)

The 2 compounds were successively administered one hour before theglucose load. All the groups were composed of 5 mice (metformin alone,compound 3 alone, metformin+compound 3, control group with carrieralone). Blood samples were taken at 0, 30, 60, 90 and 120 minutes afterthe glucose load.

After the glucose load, metformin alone caused the glycaemia area undercurve to drop by 68.5%, compound 3 alone by 54.9% and the combinationmetformin plus compound 3 by 74.4%.

These results show a major effect of the compositions of the inventionon changes in glycaemia levels.

-   -   4. Study on the additive effect of compound 4 (50 mg/kg per os)        adding to the effect of metformin (300 mg/kg per os) on changes        in glycaemia levels after an oral glucose load (OGTT) in Swiss        mice fasting for 17 h.

TABLE 4 Additive effect of compound 4 with metformin on glycaemia(mM/litre) in Swiss mice fasting for 17 h. Glycaemia Experimental Time(mn) conditions −60 0 30 60 90 120 Carrier (n = 4) 3.7 ± 0.2 4.5 ± 0.220.2 ± 2.6 18.0 ± 1.3 10.4 ± 0.2 7.8 ± 0.5 Compound 4 3.4 ± 0.2 4.0 ±0.3 18.6 ± 3.2 13.3 ± 1.5  8.8 ± 1.0 6.8 ± 1.0 (50 mg/kg) (n = 4)Metformin 4.2 ± 0.3 3.6 ± 0.3  9.5 ± 0.6 11.2 ± 1.8  9.6 ± 0.9 8.6 ± 0.7(300 mg/kg) (n = 4) Compound 4 3.5 ± 0.3 3.3 ± 0.1  8.3 ± 1.2  5.5 ± 1.4 4.8 ± 1.1 4.5 ± 0.9 (50 mg/kg) + Metformin (300 mg/kg) (n = 4)

The 2 compounds were successively administered one hour before theglucose load. All the groups were composed of 4 mice (metformin alone,compound 4 alone, metformin+compound 4, control group with the carrieralone). Blood samples were taken at 0, 30, 60, 90 and 120 minutes afterthe glucose load.

After the glucose load, metformin alone caused the glycaemia area undercurve to drop by 54.3%, compound 4 by 18.7% and the combination ofmetformin plus compound 4 by 76.4%. The effect is fully additive.

These results show a major effect of the compositions of the inventionon changes in glycaemia levels.

EXAMPLE 4 Study on the Impact of Compound 2 on the Liver, SkeletalMuscle and Pancreas

A) on the Liver

Liver cells of rats fasting for 48 hours were incubated with lactate orglutamine in the absence and in the presence of 2 mM of compound 2.Enzymatic assay of the consumption of lactate and glutamine wasperformed, the production of their metabolites was also analysed.Finally the ATP cell concentration was determined.

The results are grouped together in Table 5 below.

TABLE 5 Effects of compound 2 (2 mM) on the metabolism of lactate andglutamine in liver cells of rats fasting for 48 h NADH ExperimentalConsumption of Glucose Complete ATP mitochondrial conditions substrate(—) production oxidation concentration transport 5 mM lactate −4.49 ±0.31 2.00 ± 0.13 0.04 ± 0.26  59.2 ± 12.0 0.48 ± 0.25  5 mM lactate +−2.59 ± 0.34* 0.76 ± 0.13* 0.64 ± 0.30* 31.8 ± 8.0* 1.06 ± 0.33* 2 mMcompound 2 5 mM glutamine −1.79 ± 0.23 1.13 ± 0.17 −0.78 ± 0.42  70.8 ±11.3 — 5 mM glutamine + −2.77 ± 0.15* 0.78 ± 0.09* 0.59 ± 0.35* 34.2 ±7.6* — 2 mM compound 2 *p < 0.05, Student's test for paired data; mean ±S.E.M.; n = 6; μmoles/flask except for ATP (nanomoles per 2 preciselycut liver sections); complete oxidation: for lactate = consumption oflactate − (2 * glucose + pyruvate + alanine products), for glutamine =consumption of glutamine − (2 * glucose + pyruvate + lactate + alanine +glutamate products); mitochondrial transport of NADH such as indicatedabove.

The results show that compound 2 stimulates complete oxidation oflactate and glutamine without increasing the ATP cell level, but on thecontrary decreases this level. This suggests that decoupling occursbetween oxidation of the substrates (lactate and glutamine) which isincreased and phosphorylation of ADP to ATP which is reduced, whereasthese 2 processes are normally coupled, i.e. they normally evolve in thesame direction. The fact that the oxidation of the substrates isincreased i.e. the flow of electrons at the respiratory chain isincreased, is also evidenced by an increase in the intramitochondrialtransport of NADH; this transport is equal to the difference between theconsumption of lactate (the consumption of one molecule of lactateproduces one molecule of NADH) and twice the production of glucose(since the synthesis of one molecule of glucose requires 2 molecules ofNADH).

Study on the Metabolism of Lactate

Having regard to the fact that a 2 mM concentration of compound 2 leadsto strong inhibition of lactate consumption (Table 5), a lowerconcentration of compound 2 (0.5 mM) was used to demonstrate an increasein complete oxidation of these substrates (lactate and glutamine) bythis compound. For this demonstration, the same concentration (5 mM) of1-, 2- and 3-13C-lactate was used, and lactate consumption and 13CO2production were measured using quantitative carbon-13 NMR. Completeoxidation of a substrate was measured by the lowest CO2 value producedfrom one of its carbons. As a result, this carbon is found in greaterquantity in non-volatile products (other than CO2) formed during themetabolism of this substrate.

Table 6 below shows that the non-volatile products formed duringmetabolism of lactate are better detected when using 2-13C-lactate assubstrate. Complete oxidation of lactate can therefore be determined bymeasuring the production of 13CO2 from 2-13C-lactate.

TABLE 6 Sum of labelling of non-volatile products from lactatemetabolism in liver cells of rats fasting for 48 h Experimentalconditions 1-13C-lactate 2-13C-lactate 3-13C-lactate 5 mM lactate 2.28 ±0.05+  6.97 ± 0.10  5.92 ± 0.14+  5 mM lactate + 1.36 ± 0.09*+ 4.94 ±0.15* 4.06 ± 0.15*+ 0.5 mM compound 2 *p < 0.05 (different from control[lactate alone), +p < 0.05 (different from 2-13C-lactate), Student's ttest for paired data; mean ± S.E.M.; n = 3; μmoles of carbon 13/flask.

Table 7 below shows that compound 2 stimulates the complete oxidation oflactate although it slightly reduces (by 10%) the consumption of thissubstrate; this effect is accompanied by a reduction in the cellconcentration of ATP, this being an essential molecule for the synthesisof glucose from lactate. Decoupling of oxidative phosphorylation isthereby demonstrated.

TABLE 7 Effect of MTBL0036 (0.5 mM) on the production of 13CO2 andglucose from 2-13C-lactate (5 mM) and ATP cell concentration in theliver cells of rats fasting for 48 h Experimental Glucose 13CO2conditions production production ATP concentration 5 mM 2-13C-lactate6.17 ± 0.15  5.18 ± 0.19  243.6 ± 37.4  5 mM 2-13C-lactate + 4.69 ±0.14* 5.99 ± 0.09* 188.4 ± 25.2* 0.5 mM compound 2 *p < 0.05 (differentfrom control [lactate alone), Student's t test for paired data; mean ±S.E.M.; n = 4; μmoles/flask except for ATP (nanomoles per 6 preciselycut liver section).

Differences Between the Mechanism of Action of Compound 2 and ofMetformin:

It is to be recalled here that lactate is the main substrate of livergluconeogenesis.

It has been well proven that metformin is a moderate inhibitor ofcomplex 1 of the respiratory chain, which leads to activation of AMPKand the resulting metabolic effects, in particular inhibition of livergluconeogenesis. In rat liver cells, contrary to compound 2, metforminreduces the production of 13CO2 from 2-13C-lactate and the synthesis ofglucose. On the other hand, compound 2 is an activator of therespiratory chain subsequent to a moderate decoupling effect ofoxidative phosphorylation. This compound therefore has the potential tocorrect the mitochondrial deficiency existing in Type 2 diabetes byincreasing oxidation of the substrates and simultaneously reducing liversynthesis of glucose.

Study on Lactate Metabolism

Complete oxidation of glutamine can be examined by measuring theproduction of 13CO2 from 3-13C-glutamine (Biochem. J., 2004, 378,485-495).

Table 8 below shows that compound 2 increases the production of 13CO2from 3-13C-glutamine without increasing ATP cell concentration.

TABLE 8 Effect of compound 2 (0.5 mM) on glucose production, completeglutamine oxidation and ATP cell concentration in liver cells of ratsfasting for 48 h Experimental Glucose Production conditions productionof 13CO2 ATP concentration 5 mM 3-13C- 6.01 ± 0.09 0.23 ± 0.40 356.1 ±41.4 glutamine 5 mM 3-13C- 6.05 ± 0.30 1.86 ± 0.28* 362.9 ± 53.3 (NS)glutamine + 0.5 mM (NS) compound 2 *p < 0.5 (different from control[glutamine alone]), ANOVA assay followed by Newman Keuls assay; mean ±S.E.M.; n = 4 experiments; μmoles/flask except for ATP (nanomoles per 6precisely cut liver sections). NS = statistically non-significant.

B) On Skeletal Muscle and the Pancreas

Insulin secretion in 6 STZ-N0a rats was observed in relation toadministration of compound 2 (200 mg/kg) before (time −60 min and −30min) and after a glucose load (time 0 min). An increase in insulinsecretion was noted solely when compound 2 caused an increases in theperipheral consumption of glucose by skeletal muscle (Tables 9 to 12which give a mean of the results obtained). Tables 9 and 10 show that anincrease in muscle consumption of glucose (decreased AUC) is accompaniedby an increase in the level of circulating insulin. It is shown inTables 11 and 12 that if there is no increase in muscle consumption ofglucose, there is no increase in the level of circulating insulin.

Since the 2 occurrences are related, the conclusion can be drawn thatthe increase in glucose consumption by skeletal muscle is due tostimulation of insulin secretion of which the mechanism of action iswell known.

TABLE 9 Effects of compound 2 (200 mg/kg) on glycaemia Glycaemia(mmol/l) Experimental Time (mn) conditions −60 0 30 60 90 120 AUCcontrol (n = 6) 4.62 4.83 11.63 17.38 16.33 12.98 1048 Compound 2 4.758.75 12.97 13.15 11.37 10.13 356 (200 mg/kg) (n = 6)

TABLE 10 Effects of compound 2 (200 mg/kg) on the concentration ofcirculating insulin in rats Insulin (ng/ml) Experimental Time (mn)conditions −60 0 30 60 90 120 control (n = 6) 0.47 0.41 0.70 0.59 0.540.53 Compound 2 0.47 0.41 0.70 0.59 0.54 0.53 (200 mg/kg) (n = 6)

TABLE 11 Effects of compound 2 (25 mg/kg) on glycaemia Glycaemia(mmol/l) Experimental Time (mn) conditions −60 0 30 60 90 120 AUCcontrol (n = 6) 5.12 5.14 15.52 15.03 15.27 13.53 1025 Compound 2 5.125.23 11.15 16.21 14.36 15.33 1048 (200 mg/kg) (n = 6)

TABLE 12 Effects of compound 2 (25 mg/kg) on the concentration ofcirculating insulin in rats Insulin (ng/ml) Experimental Time (mn)conditions −60 0 30 60 90 120 control (n = 6) 1.5 1.16 2.17 1.79 1.341.33 Compound 2 1.11 1.41 1.76 1.48 1.61 1.61 (200 mg/kg) (n = 6)

Differences Between the Mechanism of Action of Compound 2 and ofMetformin:

It has been well proven that at the skeletal muscle metformin acts viaactivation of AMPK.

Compound 2 acts differently at the skeletal muscle. It acts via insulin,the secretion of which is stimulated.

1. A composition comprising metformin or a salt of metformin, apharmaceutically acceptable carrier or excipient and at least oneformula (I) compound and the enantiomers, diastereoisomers orpharmaceutically acceptable salts thereof:

where: R¹ is a group from among: —C(O)CR³R⁴CR⁵R⁶C(O)OH;—C(OH)(H)CR³R⁴CR⁵R⁶C(O)OH; —(CH₂)₄C(O)OH; or

m is an integer ranging from 0 to 8; n is 0 or 1; L¹ is a group fromamong —C(O)—; —C(O)O— or —S(O)₂—; R² is: a carbocycle group, 5-, 6 or7-membered, saturated, partly unsaturated or aromatic, substituted orunsubstituted; a polycarbocycle group, 8- to 14-membered, preferably 9-or 10-membered, saturated, partly unsaturated or aromatic, substitutedor unsubstituted; a heterocycle group, 5-, 6- or 7-membered, substitutedor unsubstituted, saturated, partly unsaturated or aromatic, possiblyhaving 1, 2 or 3 heteroatoms, the same or different, selected inparticular from among nitrogen, oxygen or sulfur; a polyheterocyclegroup, 8- to 14-membered, preferably 9- or 10-membered, substituted orunsubstituted, saturated, partly unsaturated or aromatic, possiblyhaving 1, 2 or 3 heteroatoms, the same or different, selected inparticular from among nitrogen, oxygen or sulfur; -L²-carbocycle group,the carbocycle being 5-, 6- or 7-membered, saturated, partly unsaturatedor aromatic, substituted or unsubstituted; -L²-polycarbocycle group, thepolycarbocycle being 8- to 14-membered, preferably 9- or 10-membered,saturated, partly unsaturated or aromatic, substituted or unsubstituted;-L²-heterocycle group, the heterocycle being 5-, 6- or 7-membered,substituted or unsubstituted, saturated, partly unsaturated or aromaticand possibly having 1, 2 or 3 heteroatoms, the same or different,selected in particular from among nitrogen, oxygen or sulfur;-L²-polyheterocycle group, the polyheterocycle being 8- to 14-membered,preferably 9- or 10-membered, substituted or unsubstituted, saturate,partly unsaturated or aromatic, and possibly having 1, 2 or 3heteroatoms, the same or different selected in particular from amongnitrogen, oxygen or sulfur; or hydrocarbon group, straight-chain orbranched, C₁ to C₅, preferably C₁ to C₄, preferably alkyl,straight-chain or branched, C₁ to C₅, preferably C₁ to C₄; L² being analkyl, straight-chain or branched, C₁ to C₅, preferably C₁ to C₄; R³,R⁴, R⁵ and R⁶, the same or different, are: a hydrogen atom; an alkylgroup, straight-chain or branched, C₁ to C₅, preferably C₁ to C₄; acarbocycle group, 5-, 6- or 7-membered, saturated, partly unsaturated oraromatic, substituted or unsubstituted; or R₃ and R₄, together with thecarbon atom to which they are attached, form a 5-, 6- or 7-memberedcarbocycle, substituted or unsubstituted, preferably saturated; e.g.cyclopentyl, cyclohexyl; or R₅ and R₆, together with the carbon atom towhich they are attached, form a 5-, 6- or 7-membered carbocycle,substituted or unsubstituted, preferably saturated; e.g. cyclopentyl,cyclohexyl; R⁷, the same or different, are: an alkyl, straight-chain orbranched, C₁ to C₅, preferably C₁ to C₄; e.g. methyl, ethyl, propyl,iso-propyl, butyl, ter-butyl; -L²-carbocycle group, the carbocycle being5-, 6- or 7-membered, saturated, partly unsaturated or aromatic,substituted or unsubstituted; -L²-polycarbocycle group, thepolycarbocycle being 8- to 14-membered, preferably 9- or 10-membered,saturated, partly unsaturated or aromatic, substituted or unsubstituted;-L²-heterocycle group, the heterocycle being 5-, 6- or 7-membered,substituted or unsubstituted, saturated, partly unsaturated or aromaticand possibly having 1, 2 or 3 heteroatoms, the same or different,selected in particular from among nitrogen, oxygen or sulfur; or-L²-polyheterocycle group, the polyheterocycle being 8- to 14-membered,preferably 9- or 10-membered, substituted or unsubstituted, saturated,partly unsaturated or aromatic and possibly having 1, 2 or 3heteroatoms, the same or different, selected in particular from amongnitrogen, oxygen or sulfur.
 2. The composition according to claim 1wherein R⁷, the same or different, are: an alkyl, straight-chain orbranched, C₁ to C₃; or -L²-carbocycle group, L² representing an alkyl,straight-chain or branched, C₁ to C₅, preferably C₁ to C₄; and thecarbocycle being aromatic with 5 or 6 members, e.g. phenyl, optionallysubstituted.
 3. The composition according to claim 1 wherein m is 0 or1, preferably
 0. 4. The composition according to claim 1 wherein R² is:a 6-membered aromatic carbocycle group, preferably phenyl, unsubstitutedor substituted by one or more substituents, the same or different,selected in particular from among: C₁ to C₆ alkoxy group, preferably C₁to C₃, straight-chain or branched e.g. methoxy, ethoxy, propoxy,iso-propoxy, butoxy, ter-butoxy; a halogen atom e.g. fluorine, chlorine,bromine; C₁ to C₅ alkyl group, preferably C₁ to C₄, straight-chain orbranched e.g. methyl, ethyl, propyl, butyl, iso-propyl, ter-butyl; C₁ toC₅ alkyl group, preferably C₁ to C₄, straight-chain or branched,substituted in particular by one or more halogen atoms e.g.trifluoromethyl; 5- or 6-membered heterocycle group having 1, 2 or 3heteroatoms, the same or different, selected in particular from amongnitrogen, sulfur and oxygen, preferably pyridine, unsubstituted orsubstituted by one or more substituents, the same or different selectedin particular from among: C₁ to C₆ alkoxy group, preferably C₁ to C₃,straight-chain or branched e.g. methoxy, ethoxy, propoxy, iso-propoxy,butoxy, ter-butoxy; a halogen atom e.g. fluorine, chlorine, bromine; C₁to C₅ alkyl group, preferably C₁ to C₄, straight-chain or branched e.g.methyl, ethyl, propyl, butyl, iso-propyl, ter-butyl; C₁ to C₅ alkylgroup, preferably C₁ to C₄, straight-chain or branched, substituted inparticular by one or more halogen atoms e.g. trifluoromethyl.
 5. Thecomposition according to claim 1 wherein n is
 0. 6. The compositionaccording to claim 1 wherein R³, R⁴, R⁵ and R⁶, the same or different,represent: a hydrogen atom; an alkyl group, straight-chain or branched,C₁ to C₅, preferably C₁ to C₄, e.g. methyl, ethyl, propyl, butyl,iso-propyl, ter-butyl; a carbocycle, 5-, 6- or 7-membered, saturated,partly unsaturated or aromatic, preferably saturated e.g. cyclopentyl,cyclohexyl, substituted or unsubstituted; or R³ and R⁴, together withthe carbon atom to which they are attached, form a 5-, 6- or 7-memberedcarbocycle, substituted or unsubstituted, preferably saturated; e.g.cyclopentyl, cyclohexyl; or R⁵ and R⁶, together with the carbon atom towhich they are attached, form a 5-, 6- or 7-membered carbocycle,substituted or unsubstituted, preferably saturated; e.g. cyclopentyl,cyclohexyl.
 7. The composition according to claim 1 wherein R¹ is agroup among —C(O)CR³R⁴CR⁵R⁶C(O)OH or —(CH₂)₄C(O)OH, R³, R⁴, R⁵ and R⁶being such as defined in claims 1 to
 6. 8. The composition according toclaim 1 wherein R³, R⁴, R⁵ and R⁶ each represent a hydrogen atom.
 9. Thecomposition according to claim 1 wherein the formula (I) compound isselected from among:

10-13. (canceled)
 14. A kit comprising at least one formula (I) compoundaccording to claim 1 or one of the pharmaceutically acceptable saltsthereof, and metformin or a salt of metformin for simultaneous, separateor sequential administration to a patient in need thereof.
 15. A methodfor selecting a compound for the treatment of pathologies associatedwith insulin-resistance syndrome, having an additional effect adding tothe effect of metformin, comprising the steps of: a) providing fasting,normal animals; b) measuring glycaemia in these animals; c)administering the compound to be tested to one portion of the animals,metformin to a second portion of the animals and an association ofmetformin and the compound to be tested to the last portion of theanimals; d) administering a glycose load to the animals, in particularof 2 to 4 g/kg animal body weight; e) measuring glycaemia at differenttimes; f) determining whether the compound has an additive effect to theeffect of metformin on lowering of glycaemia, in particular comparingthe glycaemia area under curve obtained for each of the compoundsadministered, and determining whether the tested compound in associationwith metformin allowed a reduction in the glycaemia area under curvecompared with metformin administered alone.
 16. The method according toclaim 15 comprising a step g) to select the compound if it respondspositively at step f).
 17. The method according to claim 15 comprising,before step a), the prior steps of: 1) determining the toxicity of thecompound to be tested; 2) providing liver cells of fasting animals; 3)incubating these cells with lactate or glutamine; 4) adding the compoundto be tested to the incubation medium; 5) performing enzymatic assay oflactate or glutamine consumption and/or of glucose production and/orassay of ATP cell concentration; 6) determining those non-toxic orscarcely toxic compounds allowing stimulation of complete lactate orglutamine oxidation and/or a reduction in ATP cell concentration; and/or7) providing animals having Type 2 diabetes; 8) administering thecompound to be tested to these animals; 9) administering a glucose loadto the animals in particular of 1 to 3 g/kg animal body weight; 10)evaluating the peripheral consumption of glucose by skeletal muscleand/or the concentration of circulating insulin; 11) determining thosenon-toxic or scarcely toxic compounds allowing an increase in theconsumption of glucose by muscle and/or an increase in the concentrationof circulating insulin, the implementation of steps a) to f) beingperformed either on the compounds responding positively at step 6) or onthe compounds responding positively at step 11), or on the compoundsresponding positively at steps 6) and 11).
 18. A method to selectnon-toxic or scarcely toxic compounds allowing the stimulation ofcomplete lactate or glutamine oxidation and/or a reduction in ATP cellconcentration, comprising the following steps: 1) determining thetoxicity of the compound to be tested; 2) providing liver cells offasting animals; 3) incubating these cells with lactate or glutamine; 4)adding the compound to be tested to the incubation medium; 5) performingenzymatic assay of the consumption of lactate or glutamine and/or of theproduction of glucose and/or assay of ATP cell concentration; 6)determining those non-toxic or scarcely toxic compounds allowingstimulation of complete lactate or glutamine oxidation and/or areduction in ATP cell concentration.
 19. The method according to claim18 comprising a step 7) to select the compound if it responds positivelyat step 6). 20-23. (canceled)
 24. A method to produce a compositioncomprising in association metformin or a salt of metformin and at leastone compound having an additive effect adding the effect of metformin,for example a formula (I) compound, the enantiomers, diastereoisomersthereof and its pharmaceutically acceptable salts, wherein there isassociated with metformin a compound having responded positively to themethod according to claim
 15. 25. A method for treating pathologiesassociated with insulin-resistance syndrome, comprising theadministration of an efficient amount of a composition according toclaim 1 to a patient in need thereof.
 26. The method according to claim25, for the treatment of diabetes, in particular Type 2 diabetes. 27.The method according to claim 25 to inhibit neoglucogenesis.